In recent years, as the aging society rapidly develops, the number of patients with senile diseases, particularly, the number of patients with bone diseases has been steadily increasing. Among them, osteoporosis is a serious problem, which often occurs in women, particularly, postmenopausal women. The accelerated bone resorption caused by the hormone imbalance or the aging process in postmenopausal women is closely involved in the development and progression of bone diseases. Therefore, bone resorption inhibitors are generally used in drug therapy for osteoporosis. However, bone resorption-inhibiting drugs being used currently, such as calcitonin preparations, estrogen preparations, vitamin K preparations, and bisphosphonate preparations, have problems with their therapeutic efficacy, immediate effectivity, side effects, dose compliance, or the like, and there has been a demand for the development of bone resorption inhibitors having the potential to become more effective drugs for treating or preventing osteoporosis.
In the living body, equilibrium is maintained between the concentrations of calcium in the bone and in the blood, and calcium constantly moves between the bone and the blood. Such movement of calcium between the bone and the blood is managed by the dynamic turnover between bone formation and bone resorption. It is known that in the bone resorption process, activated osteoclasts dissolve bone minerals such as calcium while the cysteine proteases released from the osteoclasts decompose the organic components of the bone, such as collagen, so that bone resorption is accelerated. Cysteine proteases such as cathepsins B, H, L, and S are present in the lysosomes of osteoclasts. In 1995, human cathepsin K localized in osteoclasts was isolated and found to be produced more in osteoclasts than other cathepsins (see Non Patent Literatures 1 and 2). It was also found that dwarfism patients with abnormal bone resorption have a mutation of the cathepsin K gene (see Non Patent Literature 3).
Thus, cathepsin K has attracted attention as the principal cysteine protease involved in bone resorption, and cathepsin K inhibitors are increasingly expected as bone resorption inhibitors. Aldehyde derivatives, epoxysuccinic acid derivatives (see Non Patent Literatures 4 and 5), or vinylsulfonic acid derivatives (see Non Patent Literatures 6 and 7) have been previously reported as cathepsin K-inhibiting compounds. Unfortunately, these derivatives are known to have low selectivity and to inhibit not only cathepsin K but also other cysteine proteases strongly (see Non Patent Literatures 8 to 10).
As cathepsin K has attracted attention as mentioned above, studies such as X-ray crystallography of cathepsin K and inhibitors have been actively conducted (see Non Patent Literatures 6 and 11), and some compounds are currently known to have the effect of selectively inhibiting cathepsin K (see Patent Literatures 1 to 4 and Non Patent Literatures 12 to 15).
Cytochrome P450 (hereinafter also referred to as CYP) is a typical enzyme involved in drug metabolism. In particular, CYP3A4 is a molecular species involved in the metabolism of at least 50% of the drugs being clinically used at present. The presence of a drug capable of inhibiting a drug metabolism enzyme may incur the risk of causing or enhancing side effects by preventing the enzyme from metabolizing another drug used in combination and increasing the blood concentration of the drug used in combination (see Non Patent Literatures 16 and 17). At present, therefore, checking for CYP3A4 inhibitory activity is generally performed at the initial stage of drug development studies, and inhibitory compounds are generally excluded from candidate compounds (see Non Patent Literature 17). In particular, it is considered that drugs for treating osteoporosis must have low CYP3A4 inhibitory activity because elderly people, who are to be given the drugs, often take a combination of drugs and often have decreased drug metabolism.
IC50 values (50% inhibitory concentrations) are generally used to determine the intensity of the CYP inhibitory activity. In general, the intensity is classified as a high level when IC50<1 μM, a medium level when 1 μM<IC50<10 μM, and a low level when IC50>10 μM (see Non Patent Literatures 18 and 19). Therefore, compounds with an IC50 of more than 10 μM as the intensity of CYP3A4 inhibitory activity must be selected for drugs for chronic diseases of elderly people.